Researchers revive immune cells exhausted by chronic viral infection to fight another day

Based on success in animal trials, a number of labs are intensively pursuing techniques for removing virus-sensing human helper T cells, stimulating them, and reintroducing them to reinvigorate their exhausted virus-killing henchmen.

Chronic viral infections eventually take hold because they wear the immune system out, a phenomenon immunologists describe as exhaustion.

But exhausted immune cells can be revived after the introduction of fresh cells that act like coaches giving a pep talk, researchers at Emory University’s Vaccine Center have found.

Their findings provide support for an emerging strategy for treating chronic infections: Infusing immune cells back into patients after a period of conditioning.

[As William Collinge describes them in his plain language overview of the immune system, CD8 T killer cells are like satellite dishes that have receptors on their surface for receiving signals from CD4 T helper cells (watchdog cells that sense the presence of invaders and send out APBs on them). The CD8 T killer cells then home in on the unwanted infected cells and inject poison into them.]

But a few weeks after exposure to LCMV, the mice develop a chronic infection that their immune systems cannot shake off, similar to when humans are infected by viruses like HIV and hepatitis C.

The team examined what happened to mice chronically infected with LCMV when they infused CD4 helper T cells from uninfected mice.

After the infusion, the CD8 cells in the infected mice revived and the levels of virus in their bodies decreased by a factor of four after a month.

Like coaches encouraging a tired athlete, the helper cells drove the killer cells that were already in the infected mice to emerge from exhaustion and re-engage.

The cell-based treatment was especially effective when combined with an antibody that blocks the molecule PD-1, which appears on exhausted T cells and inhibits their functioning.

Ten-Fold Reduction in Virus, Sometimes to Undetectable Levels

The antibody against PD-1 helps the exhausted killer T cells to revive, and enhances the function of the helper T cells as well: The combination reduced viral levels by roughly ten-fold, and made the virus undetectable in some mice.

"We have not seen this sharp a reduction in viral levels in this system before," says co-author Alice Kamphorst. The helper cells were all genetically engineered to recognize LCMV, a difference between mouse experiments and potential clinical application, she explains. But it may be possible to remove helper T cells from a human patient and stimulate them so that all the cells that recognize a given virus grow.

"This is an active area of research and several laboratories are looking at how best to stimulate T cells and re-introduce them," she says. In addition, she and her co-workers are examining what types of hormones or signaling molecules the helper cells provide to the killer cells. That way, that molecule could be provided directly, instead of by cell therapy, she says.

The molecule PD-1 was previously identified by Ahmed and colleagues as a target for therapy designed to re-activate exhausted immune cells. Antibodies against PD-1 have been undergoing tests in clinical studies against hepatitis C and several forms of cancer.

Collaborators from Harvard Medical School/Dana Farber Cancer Institute contributed to the paper. The research was supported by the National Institutes of Health and the Cancer Research Institute.